This is a new application for a NIDA Program Project (P-01) entitled Cocaine and Polydrug Abuse: New Medication Strategies. Cocaine abuse remains one of the nation's most serious drug abuse problems, and as yet, there are no effective anti-cocaine medications. Cocaine is often abused in combination with heroin, and dual dependence on cocaine and opioids further complicates medication based treatment. Four inter- related clinical and pre-clinical research projects are proposed to develop novel medications for the treatment of cocaine abuse and polydrug abuse. These multi-disciplinary collaborative projects involve behavioral science, endocrinology, neurobiology and pharmacology. An innovative new preclinical model of speedball (cocaine+heroin) abuse will be used to evaluate novel medication strategies, and to test the hypothesis that medication combinations targeted at both the cocaine and the opioid components of the speedball will be more effective than treatment with either anti-cocaine or anti-opioid medications alone. Acute and chronic treatment with potential anti-cocaine medications (endocrine modulators, dopamine reuptake inhibitors; dopamine agonists and antagonists ) and anti-opioid medications (high and intermediate efficacy mu agonists and a new long-acting mu antagonist) will be evaluated. In addition to pharmacological approaches, we propose to evaluate novel biologic approaches to reduce cocaine abuse that are based on our recent discoveries of cocaine-neuroendocrine interactions. We hypothesize that the acute neuroendocrine effects of cocaine may contribute to its abuse- related effects and that analysis of cocaine-endocrine interactions will guide new strategies for medications development. The temporal covariance between cocaine stimulation of anterior pituitary, gonadal and adrenal hormones will be examined in both clinical and preclinical studies. The behavioral relevance of cocaine's acute endocrine effects will be evaluated both in clinical studies and preclinical studies of biologic approaches to cocaine abuse treatment. The pharmacological mechanisms underlying cocaine's acute endocrine effects will be evaluated with selective monoamine agonists and antagonists in preclinical studies. In addition, we propose to systematically examine changes in the acute endocrine profile of cocaine produced by (a) repeated cocaine dosing in a binge pattern, (b) the addition of heroin to cocaine to simulate milieu on the efficacy of medications for cocaine abuse treatment will e examined. These studies should clarify the ways in which cocaine abuse influences and is influenced by neuroendocrine factors. Advances in understanding the neurobiological determinants of the abuse-related effects of drugs should facilitate the development of more effective treatment medications.